: We propose 1) a therapeutic vaccine trial in patients infected with human immunodeficiency virus type 1 (HIV) using a vaccine vector expressing all or portions of the HIV gag, pol and env genes, and 2) experiments culminating in an improved second generation vaccine. The vaccine vector to be employed is derived from Venezuelan equine encephalitis virus (VEE) and has been used successfully for immunization of macaques against influenza, Marburg and simian immunodeficiency viruses. The rationale for the proposed studies is that patients responding to highly active anti-retroviral therapy (HAART) have significant immune reconstitution, including generation of naive CD4 cells originating from the thymus. Studies in effectively treated HIV infected individuals have used autologous virus to boost immunity through periodic treatment interruption, and preliminary evidence suggests HIV vaccines may also stimulate immune responses in these individuals. We hypothesize that a strongly immunogenic vaccine based on the VEE vectors will stimulate and/or augment HIV specific humoral and cellular immune responses in individuals successfully treated during acute infection and possibly in individuals treated during chronic infection. If such responses were capable of suppressing HIV replication in the absence of HAART, the onset of AIDS could be substantially delayed or prevented without the cost, potential for generation of resistant mutants, and toxicity associated with life-long HAART treatment. Alternatively, augmentation of HIV-specific immunity might enhance the durability of presently available antiviral regimens and thus confer a significant clinical benefit. The program project will initially design, construct and produce a VEE vectored HIV clade B vaccine to be used in a therapeutic Phase I/II trial in HIV-infected HAART-treated individuals. Concurrently, the Program will develop improved therapeutic vaccine modalities for subsequent trial in humans.